Cartilage Hair Hypoplasia (CHH) is an autosomal recessive disorder characterized by short-limbed dwarfism and light sparse hair. The incidence of CHH is highest among the Amish of Ohio. Studies of Finnish CHH patients revealed defects in cell-mediated (T-lymphocyte) immunity. In our pilot studies of Ohio Amish CHH patients we found marked depression of in vitro lymphocyte responses to lectins and abnormally low mixed lymphocyte reactions (MLR). Serum immunoglobulin levels and in vitro B-cell function were normal. Thus, a defect in cellular immunity appears to be an integral part of CHH. In this research project we will attempt to further delineate the cellular immunologic defects in CHH individuals. Defective lymphocyte proliferative responses to lectins and alloantigens may be due to the presence of abnormal cell populations, or defects in cellular activation mechanisms. In addition, inability to proliferate in response to alloantigens may be associated with defective generation of cytotoxic cells. In this research project Amish CHH individuals, age-sex matched unaffected siblings, parents and non-Amish normal controls will be studied. We will study: 1) the lymphocyte populations and subpopulations as well as monocyte populations and their function in CHH utilizing monoclonal antibodies, and selective depletion experiments, 2) the activation of lymphocytes with a variety of activating agents (lectins, monoclonal antibody (OKT3) phorbol myristate acetate, calcium ionophore, 3) biochemical events following lymphocyte activation (Ca++ influx, amino acid transport, thymidine incorporation), 4) proliferative responses to alloantigens, 5) generation of specific alloreactive cytotoxic T-lymphocytes 6) activation in MLR of non-specific cytotoxicity (NK activity) 7) the generation of MLR suppressor cells and other aspects of cellular cytotoxicity. If CHH lymphocytes are found to have a defect in activation, study of the CHH lymphocyte, and accessible cell, may provide insights into a basic cellular defect in other less accessible cells (e.g. chondrocytes). Studies of cytotoxicity mechanisms may provide insights into the cellular requirements for these reactions. CHH may provide us with a "model system" for the study of the consequences of long term partial cellular immunodeficiency and the relative clinical significance or various cellular cytotoxicity mechanisms.